CN101691410A - Marine oligosaccharide chromic compound having function of preventing and treating insulin resistance - Google Patents
Marine oligosaccharide chromic compound having function of preventing and treating insulin resistance Download PDFInfo
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Abstract
The invention relates to an oligosaccharide metallic compound. The compound is characterized in that sugar residues of the compound consist of alpha-1, 4-L-guluronic acid; the weight average molecular weight of the compound is less than or equal to 12kD; and a molecular general formula of the compound is (C6H7O6)nCrm, wherein n is equal to 1 to 54, m is equal to 1 to 27 and the mass percentage of trivalent chromium is 0.1 to 12 percent. The preparation of the compound comprises the following steps: slowly adding chromic salt and dilute alkaline aqueous solutions in oligoguluronic acid aqueous solution under the conditions that pH is equal to 5 to 10 and temperature is between 40 and 80 DEG C; after stopping adding dilute alkaline and chromic salt aqueous solutions, carrying out heat-insulation reaction for 1 to 3h; carrying out filtration and precipitating the filtrate by ethanol with the volume 3 to 5 times that of the filtrate; carrying out static, precipitation and centrifugation; and collecting and washing the precipitate by using anhydrous ethanol to obtain the compound after drying. The oligosaccharide metallic compound has the advantages that because the raw materials are derived from marine natural products, the compound has abundant resources, easy industrialization, high safety, unique structure and ideal oral absorption and particularly integrates the advantages of marine oligosaccharide and trivalent chromium; and the compound not only has the functions of preventing insulin resistance and adjusting sugar and fat metabolism disturbance, but also has broad market and application prospects particularly in the prevention and treatment of diabetes II.
Description
Technical field
The present invention relates to a kind of sugared metal complexes and preparation method thereof and application, relate in particular to a kind of oligomerization α-L-guluronic acid chromic compound and preparation method thereof and at the control insulin resistant and improve application in the glycolipid metabolism disorder.Belong to biological technical field.
Background technology
Diabetes are a kind of complicated metabolic disorders that are subjected to multiple factor affecting, come from the interaction between environmental factors and the genetic predisposition, this disease can be brought out a series of complication, as obesity, cardiovascular and cerebrovascular diseases, hypertension, hyperlipidaemia, nervous system lesion, renal failure and tumour etc.Diabetes are divided into I type and II type, and about diabetic subject more than 95% belongs to diabetes B, and one of its basic cause of disease is an insulin resistant, and insulin resistant is through the whole process of type ii diabetes.
Studies show that, the metabolism of type ii diabetes human mitochondrion, comprise sugar in muscle and the adipocyte and fatty acid metabolism obviously impaired (Lowell B et al, Science, 2005,307:384-387).Plastosome has multiple functions such as control energy metabolism, regulation protein and fatty acid metabolism as the power factory of cell.Mitochondrial oxidative phosphorylation is dependence Mitochondrial DNA (mtDNA) coding and expresses that especially plastosome has a cover independently to transcribe and the translation system, is semiautonomous organelle in plastosome.Therefore, the situation of mtDNA and encoding gene thereof directly influences mitochondrial function.Mitochondrial metabolism is subjected to nuclear regulation and control, as peroxisome proliferator activated receptor-γ cofactor-1 α (PGC-1 α) is main transcription factor (the WilsonF et al that the regulation and control plastosome generates, Mol Cell Biol, 2003,23:1085-1094), and plastosome transcription factor A (mtTFA), nuclear breathe the factor (Goffart S et al, Exp Physiol such as (Nrf1), 2003,88 (1): 33-40).The active drugs such as thiazolidinediones that are used for the treatment of diabetes at present, as can significantly raising the expression of PGC-1a and the copy of Mitochondrial DNA than lattice row ketone, promote the oxidative phosphorylation of fat and skeletal muscle tissue and increase susceptibility (the Wilson F et al of Regular Insulin, J Clin Invest, 2004,114:1281-1289; Pagel L, et al, J BiolChem, 2008,33:22464-22472).Insulin resistant is meant that a certain amount of Regular Insulin combines the artifact effect and is lower than normally with its specific receptors, be the effect that the Regular Insulin of physiological concentration does not reach expection, mainly show as Regular Insulin and suppress liver and discharge the ability of glucose and promote surrounding tissue (mainly being skeletal muscle and fat) to absorb and utilize the ability drop of glucose.Skeletal muscle is the vital tissue of glucose metabolism, and the glucose uptake of about 80% insulin stimulating is finished by skeletal muscle.It is the major cause of body insulin resistant that the Skeletal Muscle Cell insulin sensitivity reduces, skeletal muscle is again the main target position of diabetes impairs simultaneously, just because of skeletal muscle is being brought into play main regulating effect in energy metabolism, make it become the crucial target tissue of control type ii diabetes.Because mitochondrial function is disorderly and the plastosome dyspoiesis is the important factor that participates in insulin resistant.Therefore, increase mitochondrial generation and be prevention and improve insulin resistant, and the key of control type ii diabetes (McCartyMF, Med Hypothesis, 2005,64:399-407).
Guluronic acid is one of algin molecule main component, and by the link of α 1 → 4 glycosidic link, the intramolecularly carboxyl can carry out complex coordination with each metal ion species between the poly-guluronic acid molecule.Trivalent chromic ion (Cr
3+) be human body keep euglycemia (Mertz et al, J Am Coll Nutr, 1988,17:544-547) and metabolism of fat (Abraham et al, Metabolism, 1992,41:768-771) necessary trace element is the sugar tolerance factor of generally acknowledging.Discover that the type ii diabetes people not only exists insulin resistant but also the interior chromium content of body to be lower than the normal people, replenishes trivalent chromium, quickens glycosyloxyization, promotes carbohydrate metabolism and improves the effective ways that insulin resistant is the control type ii diabetes.Because the inorganic chromium bioavailability is low, in order to improve its bioavailability, Chinese scholars has been synthesized many organic chromium complex compounds with hypoglycemic activity, as small molecules nicotinic acid chromium, chromium picolinate, chromium gluconate (publication number: CN1162590), chromium glucosaminic acid (application number: 200610039938.X) etc., but also be not engaged in the preparation and the application thereof of ocean acidic oligosaccharide chromium complex.Guluronic acid is a structural unit special in the algin molecule, by with the trivalent chromium coordination reaction, it can be prepared into oligomerization guluronic acid chromic compound (LGCr), this complex compound not only good water solubility, absorb fast but also safe, than having tangible increase mitochondrial function under the low dosage and improving the insulin resistant effect.Though disclose a kind of preparation method of Lalgine chromium among the patent ZL031097510, adopting its patented method products obtained therefrom is water-fast high-molecular weight compounds, because it is water insoluble, utilization is not easy to be absorbed by the body.LGCr provided by the invention is water-soluble oligosaccharide metal complexes, its preparation method and still be not reported in the application aspect control insulin resistant and the type ii diabetes.
Summary of the invention
The purpose of this invention is to provide a kind of oligomerization guluronic acid chromic compound and preparation method thereof, as control insulin resistant agent, can prevent and treat it because of the type ii diabetes due to the insulin resistant.
A kind of oligomerization guluronic acid chromic compound is characterized in that between its saccharide residue that by α-1, the 4-L-guluronic acid is formed, its weight-average molecular weight≤12kD, and its molecular formula can be expressed as (C
6H
7O
6)
nCr
m, wherein, n=1～54, m=1～27.Trivalent chromium quality percentage composition is 0.1～12%.
A kind of preparation method of oligomerization guluronic acid chromic compound, it is characterized in that the oligomerization guluronic acid aqueous solution under pH=5～10 and 40～80 ℃ of conditions of temperature, slowly add trivalent chromium and dilute alkaline aqueous solution, after stopping to add diluted alkaline and aqueous solution of chromium salt, continue insulation reaction 1～3h, filter, filtrate is precipitated with 3～5 times of volume of ethanol, leaves standstill, and is centrifugal, collecting precipitation precipitates through absolute ethanol washing, is drying to obtain.
Chromic salt of the present invention is meant chromium chloride, chromium acetate, chromium nitrate; Described diluted alkaline is meant dilute sodium hydroxide, potassium hydroxide, ammoniacal liquor, yellow soda ash, salt of wormwood.
Oligomerization guluronic acid chromic compound is used to prevent and treat insulin resistant.
Oligomerization guluronic acid chromic compound is used to improve carbohydrate metabolism and fat metabolic disturbance.
Oligomerization guluronic acid chromic compound is used for the type ii diabetes control.
The present invention is a raw material with the oligosaccharides guluronic acid with L-configuration, utilizes its distinctive carboxyl with itself and trivalent chromic ion ligand complex, has obtained a kind of remarkable insulin resistant and active water-soluble marine oligosaccharide compound of control type ii diabetes of improving that have.Rule of origin Yu Haiyang natural product of the present invention, have aboundresources and be easy to industrialization, safe, structure uniqueness, oral absorption are good, especially ocean acidic oligosaccharide and chromic advantage have been merged, not only have the control insulin resistant, regulate the glycolipid metabolism effect, especially aspect the preventing and treating of type ii diabetes, have wide market application foreground.
Description of drawings
Fig. 1 oligomerization guluronic acid chrome red external spectrum figure
As can be seen from Figure 1,3384.3cm
-1Be hydroxyl O-H stretching vibration peak; 2932.5cm
-1Stretching vibration peak for sugar ring C-H; 1616.2 and 1415.6cm
-1Be respectively uronic acid carboxyl-COO
-Asymmetric and symmetrical stretching vibration peak; 1326.6cm
-1Be C-O stretching vibration absorption peak in the carboxyl; 1028.3cm
-1Stretching vibration for C-O among the sugar ring C-OH; 1092.5cm
-1Be the C-O-C stretching vibration of sugar ring inner ether, 1124.4cm
-1Be C-O-C stretching vibration between adjacent saccharide residue; 947.6cm
-1Be α-non-stretching vibration peak of pyranose residue; 811.5cm
-1Be oligosaccharides L-guluronic acid charateristic avsorption band; 559.0cm
-1Be Cr-O ionic linkage charateristic avsorption band.These features show that prepared compound is oligomerization α-L-guluronic acid chromic compound (LGCr).
Embodiment
The present invention will be further described below in conjunction with embodiment and experimental result.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The method of unreceipted actual conditions in the following example usually according to the condition described in the ordinary method, or is carried out according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable to the present invention, and the usefulness that only presents a demonstration of the preferable implementation method described in the literary composition.
According to existing patent (ZL 01107952.5) technology in this laboratory, adopt the oxidizing acid edman degradation Edman from algin, to separate and obtain different molecular weight oligomerization guluronic acid (LG), and with them as the raw material for preparing oligomerization guluronic acid chromic compound (LGCr).
Embodiment 1
Taking by weighing 5g oligomerization guluronic acid (weight-average molecular weight is 3.7kD) is dissolved in the 200ml pure water, regulate pH=8 with the 2mol/L sodium hydroxide solution, under 70 ℃ of stirred in water bath, dropwise quantitatively add 2mol/L chromium trichloride solution, in dripping chromium solution, constantly keep its pH about 8 with 2mol/L sodium hydroxide, after stopping to add sodium hydroxide and chromium chloride, continue insulation 2h.Take out reaction solution, filter, 95% ethanol of 3.5 times of volumes of adding, precipitation leaves standstill, and collecting precipitation with the dehydrated alcohol dehydration, obtains oligomerization guluronic acid chromic compound at 45 ℃ of following drying under reduced pressure, actual measurement chromium content 4.1% (W/W, down together).
Embodiment 2
Taking by weighing 6g oligomerization guluronic acid (weight-average molecular weight is 1.2kD) is dissolved in the 200ml pure water, regulate pH=5 with the 1mol/L aqueous sodium hydroxide solution, under 80 ℃ of stirred in water bath, dropwise add the 2mol/L chromium trichloride aqueous solution, and keep its pH about 5 with 2mol/L sodium hydroxide, when just green flocks having occurred in the solution, stop to add sodium hydroxide and chromium chloride, continue insulation 1h.Take out reaction solution, filter, add 95% ethanol of 5 times of volumes, precipitation leaves standstill, and collecting precipitation with the dehydrated alcohol dehydration, obtains oligomerization guluronic acid chromic compound at 45 ℃ of following drying under reduced pressure, actual measurement chromium content 12.4%.
Embodiment 3
Taking by weighing 10g oligomerization guluronic acid (weight-average molecular weight is 9.7kD) is dissolved in the 500ml pure water, regulate pH=10 with the 2mol/L aqueous sodium hydroxide solution, under 60 ℃ of stirred in water bath, dropwise add 2mol/L chromium trichloride solution, and keep its pH about 10 with 2mol/L sodium hydroxide, when just green flocks having occurred in the solution, stop to add sodium hydroxide and chromium chloride, continue insulation 2h.Take out reaction solution, filter, add 95% ethanol of 3 times of volumes, precipitation leaves standstill, and collecting precipitation with the dehydrated alcohol dehydration, obtains poly-guluronic acid chromic compound at 45 ℃ of following drying under reduced pressure, actual measurement chromium content 9.2%.
Embodiment 4
Take by weighing 4g oligomerization guluronic acid (weight-average molecular weight is 5.5kD) and be dissolved in the 200ml pure water, regulate pH=9, under 50 ℃ of stirred in water bath, dropwise quantitatively add 2mol/L chromium trichloride (CrCl with the 2mol/L aqueous sodium hydroxide solution
3.6H
2O) solution, and keep its pH about 9 with 2mol/L sodium hydroxide, stop to add sodium hydroxide and chromium chloride, continue insulation 3h.Take out reaction solution, filter, add 95% ethanol of 4 times of volumes, precipitation leaves standstill, and collecting precipitation with the dehydrated alcohol dehydration, obtains oligomerization guluronic acid chromic compound at 45 ℃ of following drying under reduced pressure, actual measurement chromium content 2.3%.
Embodiment 5
Take by weighing 8g oligomerization guluronic acid (weight-average molecular weight is 7.3kD) and be dissolved in the 400ml pure water, regulate pH=6, under 40 ℃ of stirred in water bath, dropwise quantitatively add 50% chromium nitrate (Cr (NO with the 2mol/L aqueous sodium hydroxide solution
3)
3.9H
2O) aqueous solution is 4.7 milliliters, and keeps its pH about 6 with 2mol/L sodium hydroxide, stops to add sodium hydroxide and chromium chloride, continues insulation 3h.Take out reaction solution, filter, add 95% ethanol of 4 times of volumes, precipitation leaves standstill, and collecting precipitation with the dehydrated alcohol dehydration, obtains poly-guluronic acid chromic compound at 45 ℃ of following drying under reduced pressure, actual measurement chromium content 3.6%.
Embodiment 6
Take by weighing 10g oligomerization guluronic acid (weight-average molecular weight is 11.4kD) and be dissolved in the 500ml pure water, regulate pH=7, under 75 ℃ of stirred in water bath, dropwise add 10% chromium acetate (Cr (Ac) with the 2mol/L aqueous sodium hydroxide solution
3) 2.2 milliliters of the aqueous solution, and keep its pH about 7 with 2mol/L sodium hydroxide, stop to add sodium hydroxide and chromium acetate after, continue insulation 3h.Take out reaction solution, filtered while hot after the cooling, adds 95% ethanol of 3 times of volumes, leaves standstill, and centrifugal collecting precipitation with the dehydrated alcohol dehydration, at 45 ℃ of following drying under reduced pressure, obtains poly-guluronic acid chromic compound, actual measurement chromium content 0.45%.
Embodiment 7
Take by weighing 10g oligomerization guluronic acid (weight-average molecular weight is 1.5kD) and be dissolved in the 250ml pure water, regulate pH=4, under 55 ℃ of stirred in water bath, dropwise add 1% chromium acetate (CH with the 1.5mol/L aqueous sodium hydroxide solution
3COO)
32.8 milliliters of the Cr aqueous solution, and keep its pH about 4 with 1.5mol/L sodium hydroxide, stop to add sodium hydroxide and chromium acetate after, continue insulation 2h.Take out reaction solution, filtered while hot after the cooling, adds 95% ethanol of 5 times of volumes, leaves standstill, and centrifugal collecting precipitation with the dehydrated alcohol dehydration, at 45 ℃ of following drying under reduced pressure, obtains poly-guluronic acid chromic compound, actual measurement chromium content 0.06%.
The evaluated biological activity of oligomerization guluronic acid chromic compound
Press internationally recognized method with product of the present invention, estimated it to Skeletal Muscle Cell insulin sensitivity influence, to the metabolic crucial transcription factor PGC-1 α of regulation and control plastosome, mtTFA, NRF1 express influence, to the influence of mitochondria DNA copy number purpose, to the active influence of plastosome electron transport chain in the Skeletal Muscle Cell, express influence to regulating and control lipometabolic key protein PPAR-α and CPT-1, demonstrate significant control insulin resistant activity, improve carbohydrate metabolism and lipid metabolism activity, and control type ii diabetes activity.Experimental result is as follows.
1LGCr is to Skeletal Muscle Cell insulin sensitivity promoter action
The utilization Skeletal Muscle Cell makes up insulin resistant model, by with ciglitazone relatively and measure the effect of glucose transport efficiency rating LGCr.As known from Table 1, LGCr is the enhancing insulin sensitivity of concentration dependent, shows that LPCr has to improve the turn-over capacity of Skeletal Muscle Cell to glucose in 10～100umol/L.As known from Table 2, Skeletal Muscle Cell application 50umol/L LGCr after the differentiation or the effect of 20umol/L ciglitazone are after 8 hours, after stimulating 48 hours with palmitiae again, glucose transport efficient behind the mensuration insulin stimulating, show all and can improve insulin sensitivity, improve carbohydrate metabolism, point out it to have control type ii diabetes activity.
Table 1 different concns LGCr is to the promoter action of Skeletal Muscle Cell insulin sensitivity
* p＜0.05 is compared with control group (not adding palmitate); #p＜0.05 is compared with model group (adding palmitate); (n=5; X ± SD)
Table 2LGCr and ciglitazone are to the effect of Skeletal Muscle Cell insulin sensitivity
* p＜0.05 is compared with control group (not adding palmitate); #p＜0.05 is compared with model group (adding palmitate); (n=5; X ± SD)
2LGCr is to the promoter action of PGC-1 α
Skeletal Muscle Cell was with 50 μ mol/L LGCr effects 8 hours, using palmitate again stimulated 48 hours, show (table 3) through the immune protein engram analysis, the expression amount of PGC1-α extremely significantly increases (p＜0.01) in the Skeletal Muscle Cell, show that LGCr has significant promoter action to PGC1-α, show that it can increase mitochondrial generation, have the carbohydrate metabolism of improvement and disorders of lipid metabolism and control type ii diabetes activity.
Table 3LGCr is to the promoter action of Skeletal Muscle Cell PGC1-α
* p＜0.01 is compared with control group (not adding palmitate); ##p＜0.01 is compared with model group (adding palmitate); (n=5; X ± SD)
3LGCr is to the influence of Skeletal Muscle Cell mitochondrial function
Skeletal Muscle Cell is analyzed the mRNA expression of NRF1 and mtTFA and the copy situation of Mitochondrial DNA after 50 μ mol/L LGCr handle.Table 4 is the result show, compare with model group, LGCr has obvious promotion NRF1mRNA to express (P＜0.05), and promote (p＜0.01) that extremely significantly mtTFA mRNA expresses and mitochondria DNA copy number, show that further LGCr has the plastosome of raising nucleus formation, point out it to have control type ii diabetes activity.
Table 4LGCr promotes Skeletal Muscle Cell mRNA to express and promotes the mitochondria DNA copy number situation
* p＜0.01 is compared with control group; #p＜0.05 is compared with model group with ##p＜0.01; (n=5; X ± SD)
Table 5 result shows, Skeletal Muscle Cell after the differentiation is used 50umol/L LGCr effect 8 hours, using palmitate again stimulated after 48 hours, significantly (p＜0.01) improves plastosome electron transport chain composite I and the proteic activity of composite I II, show that it can increase the effect of skeletal muscle mitochondrial function, has the type ii diabetes of preventing activity.
Table 5LGCr promotes the activity of Skeletal Muscle Cell plastosome electron transport chain cpd
* p＜0.01 is compared with control group; ##p＜0.01 is compared with model group; (n=5; X ± SD)
4LGCr is to the mRNA level affects of Skeletal Muscle Cell PPAR-α and CPT-1
From table 6 data as can be seen, LGCr can obviously improve the expression of the mRNA level of Skeletal Muscle Cell peroxisome proliferator activated receptor-α (PPAR-α) and carnitine acyl transferase-1 (CPT-1).Show that it has the fats oxidn of promotion metabolic function, has the type ii diabetes of preventing activity.
Table 6LGCr is to Skeletal Muscle Cell PPAR-and CPT-1mRNA influence
* p＜0.05 is compared with control group; #p＜0.05, ##p＜0.01 is compared with model group; (n=5; X ± SD)
Through contriver's long term studies, disclosed oligomerization LGCr first for the unusual effect that promotes insulin sensitivity and control insulin resistant.Specifically, the inventor as research model, has found the enzymic activity that LGCr can significantly repair plastosome transfer chain complex body with free fatty acids (palmitate) inductive Skeletal Muscle Cell insulin resistant; LGCr can significantly increase the mitochondria DNA copy number amount of Skeletal Muscle Cell model simultaneously, these variations are accompanied by crucial transcription factor peroxisome proliferator activated receptor-γ cofactor-1a (PGC-1 α), the plastosome transcription factor A (mtTFA) of regulation and control plastosome generation and the expression rising that nuclear is breathed the factor 1 (NRF1), show that LGCr can promote significantly that plastosome generates and mitochondrial function in the skeletal muscle insulin resistant cell model; And LGCr is by the reverse peroxisome proliferator activated receptor-a relevant with the Fatty Acid Oxidation utilization (PPAR-α) that free fatty acids suppressed and the expression of carnitine acyl transferase-1 (CPT-1), promote the lipid acid β-Yang Hua, thereby improve lipid metabolism, promoted the Skeletal Muscle Cell glucose transport of insulin stimulating simultaneously, increased the susceptibility of Skeletal Muscle Cell Regular Insulin.
Product low cost product of the present invention, safe, under 10～100umol/L, can bring into play good control insulin resistant and improve glycolipid metabolism disorderly active, for the exploitation of such medicine provides new approach.
Claims (7)
1. oligomerization guluronic acid chromic compound is characterized in that between its saccharide residue that by α-1, the 4-L-guluronic acid is formed, its weight-average molecular weight≤12kD, and its molecular formula can be expressed as (C
6H
7O
6)
nCr
m, n=1～54 wherein, m=1～27.Trivalent chromium quality percentage composition is 0.1～12%.
2. the preparation method of an oligomerization guluronic acid chromic compound, it is characterized in that the oligomerization guluronic acid aqueous solution under pH=5～10 and 40～80 ℃ of conditions of temperature, slowly add trivalent chromium and dilute alkaline aqueous solution, after stopping to add diluted alkaline and aqueous solution of chromium salt, continue insulation reaction 1～3h, filter, filtrate is precipitated with 3～5 times of volume of ethanol, leaves standstill, and is centrifugal, collecting precipitation precipitates through absolute ethanol washing, is drying to obtain.
3. the described chromic salt of claim 2 is meant chromium chloride, chromium acetate, chromium nitrate.
4. the described diluted alkaline of claim 2 is dilute sodium hydroxide, potassium hydroxide, ammoniacal liquor, yellow soda ash, salt of wormwood.
5. an oligomerization guluronic acid chromic compound is characterized in that being used to prevent and treat insulin resistant.
6. an oligomerization guluronic acid chromic compound is characterized in that being used to improve carbohydrate metabolism and fat metabolic disturbance.
7. an oligomerization guluronic acid chromic compound is characterized in that being used for the type ii diabetes control.
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| CN103059154A (en) * | 2012-11-29 | 2013-04-24 | 滨州学院 | Fungal glucan oligomer chrome complex and preparation method thereof |
| WO2015000411A1 (en) * | 2013-07-02 | 2015-01-08 | 中国科学院上海药物研究所 | Sulfated polygulonic acid polysaccharide or pharmaceutical salt thereof, preparation method therefor and use thereof |
| CN105395563A (en) * | 2015-12-11 | 2016-03-16 | 青岛海洋生物医药研究院股份有限公司 | Application of oligoguluronic acid and derivative thereof in preparation of drugs and health products used for preventing and treating hyperlipidemia and complications thereof |
| US9375449B2 (en) | 2010-10-19 | 2016-06-28 | LG Bionano, LLC | Metal ion nanoclusters |
| CN108164613A (en) * | 2018-01-22 | 2018-06-15 | 中国海洋大学 | A kind of preparation and its application with the green algae polysaccharide chromium for preventing diabetes |
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| US9375449B2 (en) | 2010-10-19 | 2016-06-28 | LG Bionano, LLC | Metal ion nanoclusters |
| CN103059154A (en) * | 2012-11-29 | 2013-04-24 | 滨州学院 | Fungal glucan oligomer chrome complex and preparation method thereof |
| CN103059154B (en) * | 2012-11-29 | 2015-03-11 | 滨州学院 | Fungal glucan oligomer chrome complex and preparation method thereof |
| WO2015000411A1 (en) * | 2013-07-02 | 2015-01-08 | 中国科学院上海药物研究所 | Sulfated polygulonic acid polysaccharide or pharmaceutical salt thereof, preparation method therefor and use thereof |
| EA028655B1 (en) * | 2013-07-02 | 2017-12-29 | Шангхай Инститьют Оф Матириа Медика Чайниз Акэдеми Оф Сайнсиз | Sulfated polygulonic acid polysaccharide or pharmaceutical salt thereof, preparation method therefor and use thereof |
| US10058566B2 (en) | 2013-07-02 | 2018-08-28 | Shanghai Institute Of Materia Medica Chinese Academy Of Sciences | Sulfated polygulonic acid polysaccharide or pharmaceutical salt thereof, preparation method therefor and use thereof |
| CN105395563A (en) * | 2015-12-11 | 2016-03-16 | 青岛海洋生物医药研究院股份有限公司 | Application of oligoguluronic acid and derivative thereof in preparation of drugs and health products used for preventing and treating hyperlipidemia and complications thereof |
| CN108164613A (en) * | 2018-01-22 | 2018-06-15 | 中国海洋大学 | A kind of preparation and its application with the green algae polysaccharide chromium for preventing diabetes |
| CN109734761A (en) * | 2019-02-28 | 2019-05-10 | 福建农林大学 | A kind of preparation method and applications of Enteromorpha fucose complex compound |
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